Cyclic peptide synthetic strategies

Fig. 4. The extent to which cyclic peptide synthetic strategies may be accomplished on solid support. Note that the catechol safety-catch linker requires the inversion of the order of synthesis where the protecting groups are removed followed by cyciization.

Because conformational epitopes are not easily mimicked with linear peptides, which can elicit nonspecific antibodies, several alternative strategies such as synthetic cyclic peptides have been developed [see e.g., (18)]. A similar conformational restriction was seemingly achieved with a P-amyloid peptide that was anchored to the surface of liposomes via hydrophobic tails introduced at its both N- and C-termini. The reconstituted peptide proved highly immunogenic and elicited antibodies that could significantly prevent amyloid plaque formation in a model system (70). 

Early work in the field has established the synthetic strategies and analytical tools for such class of libraries (for reviews see refs[111 112 456]). As listed in Table 13, the first generation of cyclic peptide libraries focused on biologically active sequences such as the cell adhesion RGD motif, the antileukemic heptapeptide stylostatin, or endothelin antagonists, but also on metal-binding sequence motifs and on the de novo discovery of bioactive cyclic peptides without sequence-biased motifs. Moreover, synthetic questions were addressed such as the sequence dependency of peptide cyclization reactions (see Table 13). 

This section concludes with a description of tandem synthetic strategies (Section 14.1.6) in which sequential reactions involve combinations of steps such as dendrimer formations combined with cyclic peptides (Section 14.1.6.1), chemoselective cyclization combined with divergent syntheses (Section 14.1.6.3), and many thiol-based reactions and cyclizations (Sections 14.1.6.4—14.1.6.7) J18 ... 

The appeal of cyclic peptides as a rich source of biologically active molecules makes the synthesis of combinatorial libraries of these compounds desirable. However, few avenues for the synthesis of large arrays of cyclic peptides exist. This is primarily caused by the difficult orthogonal deprotection requirements, which require a careful choice of synthetic strategy. For example, if a solution-phase head-to-tail cyclization is undertaken (15) (Fig. 2A), the peptide must be purified at each step of the synthesis (i.e., after synthesis of the linear, cyclized protected and after deprotection) (see Note 1). 

The first case study was selected to showcase the complexity associated with the correct stereochemistry assignment of cyclic peptide natural products. Structure of cyclocinamide A underwent several modifications after its first appearance in 1997 [127]. Konopelski reported a synthetic design that utiHzed the potential of turn-inducing capability of (cyclo)Asn (Scheme 8.1) that led to the cyclocinamide derivatives, particularly aU-S isomer, without racemization [128]. The retrosynthetic strategy rehed on the use of (cyclo)Asn, as internal conformational element was... 

A different strategy devised by Evans prescribes the reaction of acyloxazo-lidinone-derived enolates (cf 98) with trisyl azide (99) to give the -substi-tuted azides such as 100 (Scheme 10.16) [82]. This electrophilic enolate amination process was highlighted in the synthesis of cyclic peptide K-13 (101), an inhibitor of angiotensin-converting enzyme [83], As an aside, another remarkable feature of this synthetic endeavor is the chemoselectivity displayed in the enolization of imide ester 98 in the presence of the methyl ester. 

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